Summary Type two immune diseases such as asthma, allergies and chronic rhinosinusitis remain important health and economical burdens. Two immune populations play critical roles in these diseases, namely Group II innate lymphoid cells (ILC2s) and Th2 cells, also critical in anti-helminth responses. ILC2s and Th2 cells have numerous common characteristics in their programs, including production of type II cytokines. Transcription factors (TFs) are key regulators for these cell programs, their functioning and identity. Understanding transcriptional and epigenetic control regulating these cells is of the highest importance for designing efficient treatments. Our recently published data show that Bcl11b is an essential TF for both ILC2 and Th2 cells during normal immune responses and in pathogenic conditions, specifically in promoting their type II program, by controlling essential TFs and downstream effector genes. In addition, our published data in the previous funding period showed that Bcl11b restricts alternate lineage programs, including type I, type III and NK gene programs in ILC2s and Th2 cells, with major impact on the immune responses and disease outcome. Strikingly, in pathogenic Th17 cells, Bcl11b plays an antipodal role, blocking the Th2 TF Gata3 and IL4 gene expression, supporting the concept that Bcl11b is essential in maintaining lineage identity and operates in a context dependent manner. In the next cycle of funding we propose to investigate the mechanisms by which Bcl11b regulates type II response in ILC2s and Thelper cells using human ILC2s and Th2 cells, and mice in the context of type II immune responses and disease models. We will establish how Bcl11b promotes type II program and restricts alternate lineage programs. We propose to delineate the common denominators and the differences in the molecular mechanisms of regulation mediated by Bcl11b in ILC2s and Th2 cells. We will investigate how Bcl11b exerts its cell specific roles by working with lineage specific TFs and chromatin modifiers and remodelers on specific enhancers and silencers to generate the adequate epigenetic status for expression or silencing of essential program genes. In addition, we will determine whether Bcl11b controls local chromatin looping to prevent or allow activity of cell specific enhancers and silencers. At the conclusion of these studies, we will have a platform for understanding the molecular components of the ILC2 and Th2 programs in mice and humans and the transcriptional and epigenetic regulatory mechanisms in normal and disease states, which will serve for better understanding of disease and future optimized treatments.